Larger effects were recorded among patients receiving concomitant nitrates [see CONTRAINDICATIONS].
Larger effects were recorded among patients receiving concomitant nitrates [see CONTRAINDICATIONS]. Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [see CONTRAINDICATIONS]. Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of VIAGRA with doxazosin, an alphaadrenergic blocking agent. In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH).
Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebosubtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg VIAGRA or matching placebo are shown in Figure 2. Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after VIAGRA or matching placebo.
There were no subjects treated with VIAGRA 25 mg who had a standing SBP <85 mmHg. There were three subjects with a decrease from baseline in standing systolic BP >30 mmHg following VIAGRA 25 mg, one subject with a decrease from baseline in standing systolic BP >30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP >30 mmHg following both VIAGRA and placebo. Of the four subjects who received VIAGRA 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). For these four subjects, the placebosubtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively. Two of these subjects had buy sildenafil citrate online canada a standing SBP <85 mmHg. Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [see CONTRAINDICATIONS]. Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of VIAGRA with doxazosin, an alphaadrenergic blocking agent. In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg.
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Thereafter, 17 subjects were treated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects).
For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebosubtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg VIAGRA or matching placebo are shown in Figure 2. Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after VIAGRA or matching placebo. There were no subjects treated with VIAGRA 25 mg who had a standing SBP <85 mmHg.
In the second study, a single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, VIAGRA 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg. For the 19 subjects who received both VIAGRA and matching placebo, the placebosubtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg VIAGRA or matching placebo are shown in Figure 3.
Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of <85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of VIAGRA 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30 mmHg following VIAGRA 50 mg and one subject with a decrease from baseline in standing systolic BP >30 mmHg following both VIAGRA 50 mg and placebo. In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH.
In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Thereafter, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with openlabel VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg). There were three subjects with a decrease from baseline in standing systolic BP >30 mmHg following VIAGRA 25 mg, one subject with a decrease from baseline in standing systolic BP >30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP >30 mmHg following both VIAGRA and placebo. Of the four subjects who received VIAGRA 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). For these four subjects, the placebosubtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively.
Two of these subjects had buy sildenafil citrate online canada a standing SBP <85 mmHg. In the second study, a single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, VIAGRA 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg.
For the 19 subjects who received both VIAGRA and matching placebo, the placebosubtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg VIAGRA or matching placebo are shown in Figure 3. Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of <85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of VIAGRA 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30 mmHg following VIAGRA 50 mg and one subject with a decrease from baseline in standing systolic BP >30 mmHg following both VIAGRA 50 mg and placebo. In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH.
For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebosubtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4. Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of <85 mmHg. All three were sildenafil white taking VIAGRA 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP >30 mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing systolic BP >30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP >30 mmHg following both VIAGRA and placebo.
While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both VIAGRA 50 mg and 100 mg. When VIAGRA 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was coadministered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see DRUG INTERACTIONS].
Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of VIAGRA on cardiac output. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of VIAGRA on the primary endpoint was statistically non-inferior to placebo. At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth- Munsell 100-hue test, with peak effects near the time of peak plasma levels. In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Thereafter, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with openlabel VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg).
For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebosubtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4.
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| Expiry Date | Check before use | Typically 2-3 years |
Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of <85 mmHg.
All three were sildenafil white taking VIAGRA 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP >30 mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing systolic BP >30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP >30 mmHg following both VIAGRA and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both VIAGRA 50 mg and 100 mg. When VIAGRA 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. VIAGRA (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was coadministered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see DRUG INTERACTIONS]. Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of VIAGRA on cardiac output. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of VIAGRA on the primary endpoint was statistically non-inferior to placebo. At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth- Munsell 100-hue test, with peak effects near the time of peak plasma levels. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry. There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers. VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-63%). When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T of 60 minutes and a mean reduction in Cmax of 29%. Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from Ndesmethylation of sildenafil, and is itself further metabolized.
An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry. There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthy volunteers. VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-63%). When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T of 60 minutes and a mean reduction in Cmax of 29%. Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes.
The major circulating metabolite results from Ndesmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active Ndesmethyl metabolite were 45% and 57%, respectively [see DOSAGE AND ADMINISTRATION, and Use In Specific Populations] In volunteers with mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered.
This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active Ndesmethyl metabolite were 45% and 57%, respectively [see DOSAGE AND ADMINISTRATION, and Use In Specific Populations] In volunteers with mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered.